The inappropriate proliferation of cells in an organism may lead to a variety of disease states. The particular symptoms will vary depending oil the type of proliferative cell and on the location of the cell. These disease states may range from cancerous malignancies when the cell is a cancer cell, to scarring when the cell type is a normal fibroblast, or to a skin disease when the proliferating cell is an epithelial or dermal cell forming a part of the integument or skin.
Proliferation of cells in various tissues of the eye can lead to impaired vision. One such example of impaired vision results from a proliferation of lens epithelial cells which remain associated with the lens capsule following cataract surgery. Specifically, extracapsular cataract extraction for the removal of cataracts frequently is accompanied by an undesired proliferation of lens epithelial cells, resulting in posterior lens capsule opacification. Virtually all pediatric patients and approximately 50% of adult patients undergoing extracapsular cataract extraction develop an opaque secondary cataract within three to five years of surgery.
Various cytotoxic agents are reported to inhibit secondary cataract formation or posterior lens capsule opacification. For example, cytotoxic agents such as 5-fluorouracil, methotrexate, colchicine, and daunomycin have been instilled into the anterior chamber of the eye to kill residual lens epithelial cells for prevention of posterior lens capsule opacification. These drugs have been delivered, e.g., by injection or with the aid of various drug delivery techniques that provide for diffusion of the drug within the eye.
A second example of vision-threatening cellular proliferation occurs following glaucoma surgery. Glaucoma encompasses a heterogeneous group of eye diseases characterized by a classical triad of symptoms: elevated intraocular pressure (IOP), optic nerve damage and progressive visual field loss. The increase in IOP is due to a decrease in the outflow of aqueous humor, the fluid in the anterior segment of the eye that is responsible for maintaining pressure balance for the entire eye. Current medical therapy for glaucoma involves the administration of one or more ocular agents, including beta-blockers (e.g., timolol), miotics (e.g., pilocarpine), adrenergic agonists (e.g., epinephrine) and carbonic anhydrase inhibitors (e.g., acetazolamide). While most glaucoma patients initially respond to drug therapy, many become refractory over time. For those individuals, maintenance of normal IOP requires surgical intervention.
Surgical techniques for the correction of glaucoma include various types of glaucoma filtering surgery (GFS), during which a drainage channel is created for aqueous humor outflow from the anterior chamber in order to lower IOP. The most successful GFS is that which uses the creation of a filtering bleb or drainage fistula, which is an elevation of the conjunctiva at the surgical site, to decrease IOP. Numerous techniques may be employed to maintain the patency of the bleb or fistula, including the use of biocompatible plastic tubes or valves, yet scarring over of the drainage channel frequently causes blockage of the bleb or fistula and a concomitant increase in IOP. Recent clinical studies have demonstrated that introduction of agents which inhibit the wound healing process can in some instances improve the success rate of GFS. These agents typically are administered by non-specific means such as application by sponge to the drainage filter tissue during the surgical procedure or by repeated, painful injections into the conjunctiva after the operation.
Drug delivery techniques which have been reported both for prevention of secondary cataracts and for GFS rely to a greater or lesser extent upon diffusion of the administered drug to the target cell site. However, the continuous movement of the aqueous fluid through the anterior chamber of the eye can alter the effective concentration of the drug at the target cell site. Thus, these delivery techniques create undesirable side effects due to the inherent activity of the modulating agent on cells other than target cells combined with the lack of specific localization to the target site, resulting in a lower effective dose at that site. For example, the non-specific delivery of potent antiproliferative agents such as mitomycin C and 5-fluorouracil often has resulted in inadequate wound healing, leakage of the aqueous humor, hypotony or very low pressure leading to further complications.
It therefore would be of interest for treatment regimens which involve a surgical procedure and for which a successful outcome depends on the modification of cell proliferation, for example, inhibition of growth of lens epithelial cells in cataract surgery and fibroblasts in glaucoma filtering surgery, to identify methods and compositions for the delivery of agents capable of modulating cell proliferation and modulating wound healing responses in a site specific manner.
Relevant Literature
Heyrman, et al. (1989), J. Cataract Refract. Surg., 5:169, describes studies of drug uptake and release by polymethylmethacrylate (PMMA) and hydrogel intraocular lenses. European Patent Application 0 443 809 A2 describes an intraocular lens (IOL) coated with a hydrophilic material and including a pharmacologically active agent. U.S. Pat. No. 4,918,165 describes an antibody-cytotoxin conjugate covalently linked to an IOL. U.S. Pat. No. 4,170,043 describes an IOL coated with a biocompatible, water-soluble film. U.S. Pat. No. 4,240,163 describes an IOL coated with a medicament.
Biodegradable microcapsules for use in the eye are disclosed in Wong (U.S. Pat. No. 4,853,224). A bioerodible polymer disc containing an aqueous mixture of mitomycin is disclosed by is disclosed by Charles et al. (1991), Ophthalmology 25 98(4):503. A biodegradable ocular implant for delivery of therapeutic agents is described by U.S. Pat. No. 4,863,457, by Lee et al. (1988), Invest. Opth. & Visual Science 29(11):1692 and by Lee et al. (1987) Ophthalmology 94:1523. Kay et al. (1986) Ophthalmic Surgery 17(12):796 describe a collagen sponge containing 5-fluorouracil for ocular use. A wafer having a diffusion limiting membrane and containing colchicine is described by Legler, et al. (1993), J. Cataract Refract. Surg. 19:462. See also Hartmann, (1990) Ophtalmologie, 4:102.
The following references also may be relevant to the subject invention: Xu, et al. (1993), Ophthal. Surgery, 24(6):382-388; Tahery and Lee (1989), J. of Ocular. Pharm., 5(2):155-179; Palmer (1991) Ophthalmology, 98:317-321; K. Mosbach (Editor ed. 1976), Methods in Enzymology, Vol. 24 Immobilized Enzymes; S. Wong (1991) Chemistry of Protein Conjugation and Crosslinking CRC; G. Pietersz (1990), G. Bioconjugate Chem. 1:89; W. J. Power, et al. (1994), J. Cat. Refract. Surg. 19:440; M. Weller, et al. (1988), International Ophthalmology 12:127; M. Bruce Shields, Textbook of Glaucoma (3rd ed. 1992), Ch. 34 and 36; and H. Alkock and F. W. Lampe (ed. 1981), Contemporary Polymer Chemistry.
The following are general articles: Maeda, et al. (1992) Bioconj. Chem. 3:351-362; Takakura and Hasida (1995) Crit. Rev. Oncol. Hematol. 18:207-231.